Filled and vulcanized elastomers are widely adopted for pharmaceutical stopper and seal applications. Elastomers have the following desirable properties: sealing and re-sealing performance, ability to be penetrated by needles without resulting in significant fragmentation, and stoppers formed from elastomers retain their physical dimensions upon high temperature sterilization. Other semi-crystalline materials, such as plastics and thermoplastic elastomers, are not able to match the elasticity, needle penetrability and dimension stability performance of amorphous elastomers. The most widely adopted elastomers for parenteral drug packaging today are halobutyl polymers due to their high gas and moisture barrier as well as low level of additives and impurities. The transition in elastomers and elastomer compositions used for the pharmaceutical applications has been driven by many factors, including the need for high cleanliness stoppers that are compatible with modern sensitive drugs, the use of high purity ingredients to minimize any chemical species that migrate out of stopper and interact with medicine (drug compatibility/turbidity), use of low amounts of clean curatives to assure drug stability/compatibility, a tight control on visible and non-visible particle contamination, and the need for low extractables/leachables.
The levels of extractable and leachable of parenteral drug packaging stoppers are being regulated today. In order to achieve good drug compatibility and minimize extractable and leachable, stopper manufacturers generally use raw materials of high cleanliness, optimize formulation to contain least amount of curing agent and other additives, and comply with good manufacturing practices (GMP) or other ISO standards.
High quality pharmaceutical stoppers today are largely made using halobutyl instead of regular butyl due to the versatile curing of the former elastomer. Regular butyl requires high dosage of sulfur and/or zinc containing curing agents and is not acceptable. Bromobutyl elastomer can be cured using low levels of zinc-free and sulfur-free curing agents and therefore, provide a high degree of cleanliness.
Brominated isobutylene para-methylstyrene (BIMSM) elastomer is a very clean elastomer that has been adopted by the industry to make stoppers for packaging expensive drugs such as antibiotics, water for injection, as well as, vaccines and biological products. Unlike halobutyl, BIMSM elastomer has a fully saturated backbone and therefore, does not need butylated hydroxylated toluene (BHT) or other antioxidant and stabilizer such as epoxidized soy bean oil (ESBO) for stabilization. The polymer also contains no oligomer, a by-product of butyl and halobutyl polymerization process. BHT, oligomer and other additives have been found to be extractables that may lead to drug incompatibility with antibiotics and other sensitive drugs. The use of natural rubber is limited due to ‘latex sensitivity’ issue. The use of other synthetic rubbers are hampered by high gas and moisture permeability, poor oxidation and heat resistance.
Apart from additives and by-products in the elastomer, curing agents adopted for vulcanization are major source of extractables for pharmaceutical stoppers. BIMSM can be cross-linked effectively through the benzylic bromine functional groups and requires less curative than halobutyl for effective crosslinking. Nevertheless any curing agents and processing additives used can potentially be extracted and cause drug incompatibility for sensitive drugs and biological products. Pharmaceutical stoppers also contain filler for mechanical reinforcement.
Additionally, prior to its intended use, pharmaceutical stoppers and seals need to be thoroughly sterilized to rid of all bacteria and micro-organisms. Known methods of sterilization include radiation sterilization and the types of radiation sterilization include electron beam, x-ray, and gamma irradiation. For electron beam radiation, a high energy electron beam accelerator is used to subject the items to relatively high doses of irradiation (higher than for x-ray or gamma). The electron beam has the ability to cause microbial death and render the material sterile to living organisms in the material. This technology is widely used as it is quick, reliable, is an on/off technology and is compatible with most material. In x-ray irradiation, an x-ray machine doses the material with ionizing energy. In gamma irradiation, Cobalt-60 or Cobalt-137 isotopes are used to generate a radiation source, which are then emitted to sterilize the items. This form of irradiation requires shielding for the operators and the emission of rays cannot be turned off as with electron beam and x-ray irradiation.
Despite these known limitations, γ-irradiation sterilization is becoming a common procedure for sterilizing seals and stoppers. Polymers, with unsaturation when subjected to γ-irradiation exposure, exhibit various degrees of crosslinking and chain scissoring at the same time. This will lead to changes in physical performances. Stoppers made using elastomers that are vulnerable to γ-irradiation sterilization will suffer from changes in its hardness, compression set, tear and tensile strength etc., which can subsequently impact stopper performances.
Because of these concerns, the industry is constantly looking to find both elastomers and compounded elastomers having improved resistance to deterioration during sterilization and reduced leachables.